purpose. To compare the rates of progression of visual field defects in glaucoma
patients, by using the Glaucoma Change Probability program based on
pattern deviation and total deviation probability maps.

methods. The incidence of progression of visual field loss among 67 eyes of 56
glaucoma patients with an average of 6 years of follow-up was estimated
by applying the criteria set by the Early Manifest Glaucoma Treatment
study, which uses the output from the Glaucoma Change Probability (GCP)
program of the Humphrey Field Analyzer (San Leandro, CA) based on
pattern deviation probability maps. This incidence estimate was
compared with one obtained by applying the same criteria but using the
GCP program based on total deviation probability maps.

results. The 6-year incidence of progression among patients with glaucoma was
23.2% and 35.7% using the GCP program based on pattern deviation and
total deviation probability maps, respectively. Not all patients in
whom visual field loss progressed according to pattern deviation also
showed progression according to total deviation.

conclusions. The GCP program based on pattern deviation probability maps appears to
screen out patients in whom progression of visual field defects may be
due to diffuse loss from cataract, but the pattern deviation maps may
also be identifying other types of field loss not detected by the total
deviation maps.

The ability to detect progression of visual field defects in
patients with glaucoma is important for clinicians who treat patients
and for researchers who conduct clinical trials of treatments for the
disease. Several statistical methods for analyzing longitudinal visual
field data have been proposed, but there is little agreement about
which approaches best reflect true progression of the
disease.1234567891011121314 A number of clinical trials are underway to
test various treatments for glaucoma, and each uses a different
analytic method for detecting visual field
progression.1516171819 The problem with evaluating these
methods is that there is no gold standard against which to validate
them. In addition, glaucoma patients in this age group often have media
opacities that progress, making it difficult to separate visual field
changes due to glaucoma from those due to cataract.

The printout of the Humphrey Field Analyzer (San Leandro, CA) for an
individual visual field test result displays a total deviation and a
pattern deviation probability map.20 The total deviation
map gives the differences between the threshold values observed on the
test- and age-specific normal threshold values at each location in the
field. The pattern deviation map takes the difference between each
observed threshold and the average threshold across the entire field
and displays the difference between these values and age-specific
normal threshold differences at each location. The rationale for this
approach is that the pattern deviation values remove the diffuse field
loss due to cataract and make the localized patterns observed after its
removal more likely to be due to glaucoma than cataract. Such an
outcome has been observed after cataract surgery when mean deviation
values improved but corrected pattern standard deviations
worsened.21

The Glaucoma Change Probability (GCP) program (Humphrey) compares the
average of results of two baseline full-threshold visual field tests
against the current test on a point-by-point basis. In the commercial
version, this comparison is based on comparing total deviation
probability maps.20 In the Early Manifest Glaucoma
Treatment trial, output from the GCP program of the Humphrey Field
Analyzer was used to classify progression of visual field
defects.1922 In that trial, the GCP program was used
based on data from the pattern deviation probability maps. The reason
for using these rather than the total deviation maps is that the
pattern deviation approach reduces the likelihood of identifying
changes due to cataract progression in the absence of visual field
changes due to glaucoma. The evidence for this comes from a study of
patients with glaucoma in which the visual fields tested before and
after cataract surgery were compared using the GCP
program.23 The differences between fields before and after
cataract surgery were much greater when using total rather than pattern
deviation maps.

In this study, we applied both types of GCP programs to a common set of
annual visual fields of patients with glaucoma observed for an average
of 6 years to estimate and compare the incidence of progression using
the two methods. The idea was to see whether the incidence of
progression using the pattern deviation maps would be lower than if the
total deviation maps were used, whether incident cases based on the
pattern deviation maps would be a subset of those from the total
deviation maps, and whether one or the other agreed more closely with a
clinical assessment of visual field progression in these patients.

Methods

The Glaucoma Screening Study was a longitudinal study at the
Wilmer Eye Institute, sponsored by the National Eye Institute, to
identify early risk factors for the development of glaucomatous field
loss in patients with ocular hypertension.2425 Primary
open-angle glaucoma was diagnosed during a comprehensive examination by
one of four study ophthalmologists. All patients with glaucoma had
intraocular pressure higher than 21 mm Hg on at least two occasions
before treatment. Visual field testing was performed annually using
Program 30-2 of the Humphrey Field Analyzer. This is a full-threshold
test of the central 30° field using a stimulus of size III and was
administered by trained technicians according to the study protocol for
testing.26 Patients included in this study were those in
whom glaucoma had been diagnosed and who had at least 5 years of
follow-up (at least six visual field tests), whose visual acuity was
20/100 or better, and whose first two field test results in the study
were outside normal limits on the Glaucoma Hemifield
Test.101819 Only 0.6% of fields had false-positive
response rates of 50% or more, 2.2% had false-negative responses of
50% or more, and 3.8% had fixation losses of 50% or more. Fields
were not excluded on the basis of reliability criteria, because only a
small fraction of fields were grossly unreliable and because there was
no a priori reason to think that the comparison of the two methods
would be differentially affected by reliability.

The clinical assessment of visual field progression was performed by
two fellowship-trained glaucoma specialists who reviewed the sequence
of visual fields for each patient. The clinicians were provided with
individual printouts from the Humphrey programs but were not given the
GCP printouts or any other clinical information. Each sequence of
fields was classified as “definite progression,” “possible
progression,” “stable-improved,” or “too unreliable to
assess.” Each clinician independently assigned the sequences to one
of the categories. Differences between the two clinicians were
adjudicated, and one clinical assessment of progression was produced
from this adjudication. To compare the clinical assessment with the
statistical methods, eyes were classified as having incident
progression if both clinicians agreed that there had been “definite
progression.”

The classification system designed for the Early Manifest Glaucoma
Treatment study was used to identify incident progression of visual
field defects. Progression was defined as a statistically significant
deterioration (P < 0.05) on the pattern deviation
probability maps of the GCP printouts in at least three locations (not
necessarily contiguous) with confirmation on two consecutive tests in
the same locations. Improvement was defined as three locations that
improved (P < 0.05), and these improvements were
confirmed on two further tests. The test results were transferred to
Statpac for Windows (Humphrey) for analysis using the
commercially available GCP program. Humphrey Instruments also kindly
provided us with a version of Statpac for Windows software to analyze
data from pattern deviation maps. This definition of progression was
also applied to the GCP output based on commercially available total
deviation probability maps.

In the printout of the GCP for pattern deviation, the follow-up
probability maps sometimes have Xs at specific locations. The key on
the printout identifies these locations as “not in database,”
indicating that the baseline threshold values are too low or too high
for making effective comparisons. These locations were not used to
assess whether at least three locations had changed significantly from
the baseline values. If all locations in the sequence of the field for
an eye had these markings, the eye was classified as having no
progression, but an analysis of incidence was also performed in which
these eyes were removed from the numerator and denominator.

Written informed consent for participation in the Glaucoma Screening
Study was obtained from each patient. The study was given ethical
approval by the Joint Committee on Clinical Investigations of the Johns
Hopkins School of Medicine in compliance with the Declaration of
Helsinki regarding the protection of human subjects.

Results

The study population has been described in detail
elsewhere.101819 Briefly, 67 eyes of 56 patients with
glaucoma had two baseline visual fields that were outside normal limits
on the Glaucoma Hemifield Test and had at least 5 years of follow-up
field tests (median follow-up was 6.3 years). Forty-five percent of
patients were African-American, and the average age at baseline
was 62 ± 10 years. Ten percent underwent cataract surgery during
this period, of whom 9% underwent combined cataract and glaucoma
surgery. The average baseline vertical cup-to-disc ratio was 0.62.
According to the classification of Hodapp et al.,27 28%
of baseline fields had early, 30% had moderate, and 42% had severe
defects. The average baseline mean deviation was −7.43 dB, and the
average corrected pattern SD was 7.09 dB. Agreement between the two
clinicians about progression of field loss was excellent, κ = 0.87
(95% confidence interval [CI], 0.63, 0.99), and adjudication was
required for only 3 of the 67 eyes for classification as definite
progression versus all other categories.

Based on clinical assessment, 20.9% of eyes and 23.2% of
patients had progression of visual field loss during the 6 years of
follow-up (Table 1) . The incidence was the same using the GCP pattern deviation
maps. However, the incidence was 32.8% of eyes and 35.7% of patients
if total deviation maps were used (a 50% higher incidence than pattern
deviation estimates). The rates of improvement of visual fields were
similar for all three methods, with the total deviation map rates being
slightly higher than clinical assessment or progression based on
pattern deviation maps but not reaching statistical significance. There
were nine eyes of nine patients in whom overall threshold values were
too low at baseline to allow a comparison with subsequent fields using
pattern deviation maps. If these patients were removed from the
numerator and denominator, the incidence of progression using the
pattern deviation maps was 24.1% of eyes and 27.7% of patients.

The agreement between total and pattern deviation probability map
methods for estimating incident progression of field loss was
relatively poor. The agreement was 79.1%, but the κ statistic was
0.48 (95% CI: 0.24, 0.70), indicating only moderate agreement between
the two methods (Table 2) . Not all eyes identified by the total deviation method were identified
by the pattern deviation method. When the nine eyes of nine patients
with baseline thresholds that were too low to allow a follow-up
comparison with the pattern deviation maps were removed from the
analysis, the agreement was 79.3% and the κ 0.51 (95% CI: 0.26,
0.76).

Although the incidence of progression was the same for clinical
assessment and pattern deviation maps, half of these were not in the
same eyes (Table 3) .19 The incidence of progression was higher for total
deviation maps than for clinical assessment, but the agreement with
clinical assessment was slightly better for the total than for the
pattern deviation method based on κ statistics. If clinical
assessment is considered the gold standard, then the sensitivity and
specificity of total deviation maps were both 79%. The sensitivity and
specificity for pattern deviation were 50% and 87%, respectively.
When the nine eyes of nine patients with baseline thresholds which were
too low to allow a comparison on the pattern deviation maps were
removed from the denominator, the κ statistic was 0.41, and the
sensitivity and specificity against clinical assessment were 58% and
85%, respectively.

The patients identified as having progression of visual field defects
by the total deviation but not the pattern deviation program had the
same average change in visual acuity (0.16 log minimum angle of
resolution [logMAR] decrease) as those identified by the pattern and
the total deviation maps (0.17 logMAR decrease), and the percentage of
eyes with three or more lines of acuity lost during the follow-up was
36% in each group. Among those who had cataract surgery, visual acuity
increased by an average of 0.02 logMAR during the study and in no
patient did acuity increase by more than two lines. None of these
patients was classified as having improvement by either method. Half
were classified as having progression of field loss by the total
deviation program, one of whom was also classified as having
progression by the pattern deviation program.

Discussion

The study by Bengtsson et al.23 showed that the
change in pattern deviation maps between field tests performed before
and after cataract surgery was much less than for total deviation maps.
This suggests that the GCP program based on pattern deviation maps
would be less affected by increasing media opacities than the one based
on total deviation maps. However, this is the first time the two
programs have been applied to a common longitudinal set of visual
fields and the incidence of field loss progression compared. The
incidence of progression using the pattern deviations maps was a third
lower than the incidence based on total deviation maps. However, there
were three patients who were identified as having progressive field
defects on the pattern but not on the total deviation maps. Two of
these patients had fields that produced unreliable results (one with
abnormally high sensitivity). The third patient had reliable results in
fields with three noncontiguous edge points that showed progression of
field loss on pattern deviation maps but showed no progression on the
total deviation maps. Because only one patient had unexplained
disparate findings, our results support the notion that some
progression detected on the total deviation maps was due to progression
of cataract rather than glaucoma.

Agreement between clinicians in this study was excellent when
visual field sequences were classified into two categories alone. The
agreement was moderate (κ 0.69) for classification into four
categories. Unlike this study, Werner et al.2 found that
agreement was better between statistical methods than between clinical
observers. Agreement, as measured by κ statistics, ranged from 0.48
to 0.61 among three observers using two categories of
classification,11 but it is difficult to compare results
because agreement depends on the type and number of categories, the
patient population, and the way in which agreement is measured.

It is difficult to know whether the pattern deviation maps
screened out patients with increasing media opacification, because
clinical documentation of cataract progression was not available for
these patients. Because visual acuity was measured each time visual
field testing was performed, a change in visual acuity was used as a
proxy for media opacification. By visual acuity criteria, there was no
evidence that those with a larger change in acuity were classified by
the total deviation but not the pattern deviation method, as would be
expected if the acuity changes reflected media opacification. There was
modest agreement between clinical assessment of progression and the
GCP. The agreement was slightly, but not significantly, higher using
total deviation rather than pattern deviation maps. The clinicians had
no information about cataract in these patients but had visual acuity
and mean deviation data available to them, although these are poor
proxies for true but more subtle media opacification.

In patients who had cataract surgery during follow-up, visual acuity
improved only slightly, but this improvement did not correlate with
improvement in visual fields as measured by the GCP based on either
type of probability map. There was also no overlap in improvement in
fields between clinical assessment and either of the two methods. It
appears that improvement was probably an artifact of the variability of
visual field testing in this study.

An additional consideration in using pattern deviation maps for
measuring progression is that the program could not assess 13% of eyes
in which baseline threshold values were considered too low (or too
high) to make an accurate assessment of change over time. Eight of nine
of these eyes had baseline mean deviations that ranged from −17 to−
23 dB. One eye had baseline thresholds that were too high (mean
deviation of +3 and +2 dB). This may be a reasonable caution regarding
assessment of progression and may help indicate to clinicians that a
different testing strategy may be appropriate for these patients with
more advanced disease. This caution is not provided with the current
total deviation–based program.

In summary, the GCP program based on pattern deviation probability maps
is likely to screen out some patients with increasing media opacities
but with stable glaucoma. The program also identifies patients who have
baseline thresholds that are low enough to make it difficult to assess
further progression using the 30° full-threshold test. The program is
not yet available commercially. Although the program appears promising,
a study comparing the two methods using longitudinal data of adequate
follow-up with well-documented media opacities and visual fields and
perhaps simulation studies would be helpful in assessing whether
pattern deviation maps are the preferred way to identify visual
field defect progression in patients with glaucoma.

Supported by Grants EY-11592, EY-09130, EY-03605, and RR-04060 of the National Institutes of Health, Bethesda, Maryland.